Substituted benzimidazoles, processes for their preparation, their use as medicaments, and medicaments comprising them

ABSTRACT

The invention relates to the use of compounds of formula I for the production of a medicament for the treatment of illnesses which can be influenced by inhibition of the Na+/H+ exchanger, and to a medicament comprising them:                    
     in which R1 to R9 have the meanings shown in the claims.

This application claims the benefit of the filing date of German PatentApplication No. 10060292.4, filed on Dec. 5, 2000, which application ishereby incorporated by reference.

The invention relates to substituted benzimidazoles of formula I:

in which:

R1 and R5 are, independently of one another, F, Cl, Br, I, CN, alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine; or

R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

R1 and R5 are, independently of one another, OH or O-alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; or

R1 and R5 are, independently of one another, OCOR10, NR11R12, COR13,COOH, COOR14, CONR11R12, or —(O)_(n)—SO_(m)R15, in which n is 0 or 1 andm is 0, 1, or 2; or

R1 and R5 are O-phenyl, in which phenyl is unsubstituted or substitutedby one to three substituents selected, independently of one another,from F, Cl, Br, I, alkyl having 1 to 4 carbon atoms, OH, O-alkyl having1 to 4 carbon atoms, NR16R17, CN, or (C₁-C₄)-alkylsulfonyl, in which thealkyl groups are unsubstituted or partially or completely substituted byfluorine;

R16 and R17 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine;

R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

R11 and R12 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine, and at least one CH₂ group of said alkyl isoptionally replaced by O or NR18; or

R11 and R12, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring; or

R11 and R12 are, independently of one another, COR19 or SO₂R20;

R18, R19, and R20 are, independently of one another, H or alkyl having 1to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine;

R13 and R14 are alkyl having 1 to 4 carbon atoms, which is unsubstitutedor partially or completely substituted by fluorine;

R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4 carbonatoms and are unsubstituted or partially or completely substituted byfluorine; or

R15 is OH or NR21 R22;

R21 and R22 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine, and at least one CH₂ group of said alkyl isoptionally replaced by O or NR23;

R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

R21 and R22, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring;

but R1 and R5 cannot simultaneously be Cl or CH₃;

R2, R3, and R4 are H or one of the radicals R2, R3, or R4 is optionallyF;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, l,CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4 carbonatoms and are unsubstituted or partially or completely substituted byfluorine; or

R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

R6, R7, R8, and R9 are, independently of one another, OH, OCOR24, orNR25R26;

R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

R25 and R26 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; or

R25 and R26 are COR27; or

R25 and R26, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring, and at least one CH₂ group thereof isoptionally replaced by O or NR18;

R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

a pharmaceutically tolerable salt or trifluoroacetate thereof.

Other embodiments of compounds of formula I are those in which:

R1 and R5 are, independently of one another, F, Cl, Br, CN, alkyl having1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkyl having 3 to 7carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF₃, OCH₂CF₃,OCF₂CF₃, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, —O_(m)—SO₂R15,or O-phenyl;

m is 0 or 1;

R10 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R11 and R12 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, and at least one CH₂ group of saidalkyl is optionally replaced by O or NR18; or

R11 and R12, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring; or

R11 and R12 are, independently of one another, COR19 or SO₂R20;

R18, R19, and R20 are, independently of one another, H, alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R13 and R14 are, independently of one another, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R15 is alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, OH,O-alkyl having 1 to 4 carbon atoms, OCF₃, OCH₂CF₃, OCF₂CF₃, or NR21R22;

R21 and R22 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

R21 and R22, together with the nitrogen atom to which they are bonded,are —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂—, or —(CH₂)₂—N—R30—(CH₂)₂;

R30 is H, CH₃, or CF₃;

but R1 and R5 cannot simultaneously be Cl or CH₃;

R2, R3, and R4 are H or one of the radicals R2, R3, or R4 is optionallyF;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I,CN, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkylhaving 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms,OCF₃, OCH₂CF₃, OCF₂CF₃, OCOR24, or NR25R26;

R24 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R25 and R26 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, or COR27; or

R25 and R26, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring;

R27 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

a pharmaceutically tolerable salt or trifluoroacetate thereof.

Another embodiment of compounds of formula I are those in which:

R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl,ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl,OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino,N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14,CONR11R12, SO₂R15, or O-phenyl;

R11 and R12 are, independently of one another, H, methyl, or ethyl;

R14 is methyl or ethyl;

R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

R21 and R22 are, independently of one another, H or methyl;

but R1 and R5 cannot simultaneously be Cl or CH₃;

R2, R3, and R4 are H;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, CN, CH₃,C₂H₅isopropyl, CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

R25 and R26 are, independently of one another, H, methyl, or acetyl; or

a pharmaceutically tolerable salt or trifluoroacetate thereof.

Another embodiment of compounds of formula I are those in which:

R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl,ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl,OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino,N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14,CONR11R12, SO₂R15, or O-phenyl;

R11 and R12 are, independently of one another, H, methyl, or ethyl;

R14 is methyl or ethyl;

R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

R21 and R22 are, independently of one another, H or methyl;

but R1 and R5 cannot simultaneously be Cl or CH₃;

R2, R3, and R4 are H;

R6 and R9 are, independently of one another, H, F, Cl, CN, CH₃, CF₃,cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

R25 and R26 are, independently of one another, H, methyl, or acetyl;

R7 and R8 are, independently of one another, H, F, or OH; or

a pharmaceutically tolerable salt or trifluoroacetate thereof.

Examples of compounds of formula I are:

(1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;

2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;

(1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;

(1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;

(2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;

(2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;

(1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;

(1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;

2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;

2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;

2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;

2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;

2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazole;

2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;

2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;

(1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;

(1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;

(1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and

(1H-benzimidazol-2-yl)-o-tolylamine; or

a pharmaceutically tolerable salt or trifluoroacetate thereof.

In addition, the invention comprises the use of substitutedbenzimidazoles of formula I for the production of a medicament for thetreatment of diseases which are influenced by the NHE3 exchangeinhibitor, in which:

R1 and R5 are, independently of one another, H , F, Cl, Br, I, CN, alkylhaving 1 to 4 carbon atoms, in which alkyl is unsubstituted or partiallyor completely substituted by fluorine; or

R1 and R5 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

R1 and R5 are OH or O-alkyl having 1 to 4 carbon atoms, in which alkylis unsubstituted or partially or completely substituted by fluorine; or

R1 and R5 are OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, or—(O)_(n)—SO_(m)R15, in which n is 0 or 1 and m is 0, 1, or 2; or

R1 and R5 are O-phenyl, in which phenyl is unsubstituted or substitutedby one to three substituents selected from F, Cl, Br, I, alkyl having 1to 4 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms, NR16R17, CN,or (C₁-C₄)-alkylsulfonyl, in which the alkyl groups are unsubstituted orpartially or completely substituted by fluorine;

R16 and R17 are H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

R10 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

R11 and R12 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine, and at least one CH₂ group of said alkyl isoptionally replaced by O or NR18; or

R11 and R12, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring; or

R11 and R12 are COR19 or SO₂R20;

R18, R19, and R20 are, independently of one another, H or alkyl having 1to 4 carbon atoms, in which alkyl is unsubstituted or partially orcompletely substituted by fluorine;

R13 and R14 are alkyl having 1 to 4 carbon atoms, which is unsubstitutedor partially or completely substituted by fluorine;

R15 is alkyl or O-alkyl, in which the alkyl groups have 1 to 4 carbonatoms and are unsubstituted or partially or completely substituted byfluorine; or

R15 is OH or NR21R22;

R21 and R22 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine, and at least one CH₂ group of said alkyl isoptionally replaced by O— or NR23;

R23 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

R21 and R22, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring;

R2, R3, and R4 are, independently of one another, H or F;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I,CN, alkyl, or O-alkyl, in which the alkyl groups have 1 to 4 carbonatoms and are unsubstituted or partially or completely substituted byfluorine; or

R6, R7, R8, and R9 are cycloalkyl having 3 to 7 carbon atoms, which isunsubstituted or partially or completely substituted by fluorine; or

R6, R7, R8, and R9 are OH, OCOR24, or NR25R26;

R24 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine;

R25 and R26 are, independently of one another, H or alkyl having 1 to 4carbon atoms, in which alkyl is unsubstituted or partially or completelysubstituted by fluorine; or

R25 and R26 are COR27; or

R25 and R26, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring, and at least one CH₂ group thereof isoptionally replaced by O or NR18;

R27 is H or alkyl having 1 to 4 carbon atoms, in which alkyl isunsubstituted or partially or completely substituted by fluorine; or

a pharmaceutically tolerable salt thereof.

Other embodiments comprise the use of compounds of formula I in which:

R1 and R5 are, independently of one another, H, F, Cl, Br, CN, alkylhaving 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkyl having 3 to7 carbon atoms, O-alkyl having 1 to 4 carbon atoms, OH, OCF₃, OCH₂CF₃,OCF₂CF₃, OCOR10, NR11R12, COR13, COOH, COOR14, CONR11R12, —O_(m)—SO₂R15,or O-phenyl;

m is 0 or 1;

R10 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R11 and R12 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, and at least one CH₂ group of saidalkyl is optionally replaced by O or NR18; or

R11 and R12, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring; or

R11 and R12 are COR19 or SO₂R20;

R18, R19, and R20 are, independently of one another, H or alkyl having 1to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R13 and R14 are alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, orCF₂CF₃;

R15 is alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, OH,O-alkyl having 1 to 4 carbon atoms, OCF₃, OCH₂CF₃, OCF₂CF₃, or NR21R22;

R21 and R22 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

R21 and R22, together with the nitrogen atom to which they are bonded,are —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₂—O—(CH₂)₂—, or —(CH₂)₂—N—R30—(CH₂)₂;

R30 is H, CH₃, or CF₃;

but R1 and R5 cannot simultaneously be Cl or CH₃, and at most one of thesubstituents R1 and R5 is hydrogen;

R2, R3, and R4 are, independently of one another, H or F;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, Br, I,CN, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, cycloalkylhaving 3 to 7 carbon atoms, OH, O-alkyl having 1 to 4 carbon atoms,OCF₃, OCH₂CF₃, OCF₂CF₃, OCOR24, or NR25R26;

R24 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃;

R25 and R26 are, independently of one another, H, alkyl having 1 to 4carbon atoms, CF₃, CH₂CF₃, CF₂CF₃, or COR27; or

R25 and R26, together with the nitrogen atom to which they are bonded,form a 5-, 6-, or 7-membered ring;

R27 is H, alkyl having 1 to 4 carbon atoms, CF₃, CH₂CF₃, or CF₂CF₃; or

a pharmaceutically tolerable salt thereof.

Other embodiments comprise the use of compounds of formula I in which:

R1 and R5 are, independently of one another, H, F, Cl, Br, CN, methyl,ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl,OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino,N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14,CONR11R12, SO₂R15, or O-phenyl;

R11 and R12 are, independently of one another, H, methyl, or ethyl;

R14 is methyl or ethyl;

R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

R21 and R22 are, independently of one another, H or methyl;

but R1 and R5 cannot simultaneously be Cl or CH₃, and at most one of thesubstituents R1 and R5 is hydrogen;

R2,R3,and R4are H;

R6, R7, R8, and R9 are, independently of one another, H, F, Cl, CN, CH₃,C₂H₅, isopropyl, CF₃, cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

R25 and R26 are, independently of one another, H, methyl, or acetyl; or

a pharmaceutically tolerable salt thereof.

Another embodiment comprises the use of compounds of formula I in which:

R1 and R5 are, independently of one another, F, Cl, Br, CN, methyl,ethyl, isopropyl, CF₃, cyclopropyl, OH, O-methyl, O-ethyl, O-isopropyl,OCF₃, O-acetyl, NH₂, N(CH₃)₂, N(CH₂CH₃)₂, N-pyrrolidino, N-piperidino,N-morpholino, N-(N′-methyl)-piperazino, NHSO₂Me, acetyl, COOH, COOR14,CONR11R12, SO₂R15, or O-phenyl;

R11 and R12 are, independently of one another, H, methyl, or ethyl;

R14 is methyl or ethyl;

R15 is CH₃, CF₃, OH, OCH₃, OCF₃, or NR21R22;

R21 and R22 are, independently of one another, H or methyl;

but R1 and R5 cannot simultaneously be Cl or CH₃, and at most one of thesubstituents R1 and R5 is hydrogen;

R2, R3, and R4 are H;

R6 and R9 are, independently of one another, H, F, Cl, CN, CH₃, CF₃,cyclopropyl, OH, OCH₃, OCF₃, O-acetyl, or NR25R26;

R25 and R26 are, independently of one another, H, methyl, or acetyl;

R7 and R8 are, independently of one another, H, F, or OH; or

a pharmaceutically tolerable salt thereof.

Examples comprising the use of compounds of formula I are:

1: (1H-benzimidazol-2-yl)-(2,6-dichlorophenyl)amine;

2: 2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;

3: (1H-benzimidazol-2-yl)-(2,6-dimethylphenyl)amine;

4: (1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;

5: (2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;

6: (2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;

7: (1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;

8: (1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;

9: 2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;

10: 2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;

11: 2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;

12: 2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;

13: 2-(2,6-dichlorophenylamino)-5 hydroxybenzimidazole;

14: 2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole;

15: 2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole;

16: (1H-benzimidazol-2-yl)-(2-chlorophenyl)amine;

17: (1H-benzimidazol-2-yl)-(2-trifluoromethylphenyl)amine;

18: (1H-benzimidazol-2-yl)-(2-bromophenyl)amine; and

19: (1H-benzimidazol-2-yl)-o-tolylamine; or

a pharmaceutically tolerable salt thereof.

If compounds of formula I contain one or more centers of asymmetry,these can have either the S or the R configuration. The compounds can bepresent as optical isomers, as diastereomers, as racemates, or asmixtures thereof.

Compounds of formula I can furthermore be present as tautomers or as amixture of tautomeric structures. In the case of substitution on thecorresponding N atoms of the benzimidazole structure, the compounds canbe present in the form of the various double bond isomers or as amixture of the double bond isomers.

The designated alkyl radicals or partially or completely fluorinatedalkyl radicals can be either straight-chain or branched.

CH₂ units are also the terminal CH₃ groups in an alkyl chain, which areinterpreted in this connection as CH₂—H groups.

The expression “5-, 6-, or 7-membered ring” represents a 5-membered to7-membered heterocyclic ring comprising at least one alkyl orheteroatom. Examples of heteroatoms are nitrogen, oxygen, and sulfur. Ifmultiple heteroatoms are contained, these can be identical or different.

Methods for the preparation of the compounds used are also described.Thus, compounds of formula I can be prepared in the manner known to theperson skilled in the art from the underlying isothiocyanates of formulaII and the corresponding phenylenediamines of formula III.

The thiourea intermediately formed here is cyclized to the correspondingcompounds of formula I by means of mercury(II) oxide (J. Med. Chem., 18,90-99 (1975)), methyl iodide (Synthesis, 41-42 (1974)), or carbodiimide(Synthesis, 864-865 (1977)). The isothiocyanates of formula II usedhere, if not commercially obtainable, can be prepared in the mannerknown from the literature from the corresponding anilines by the methodsknown to the person skilled in the art, e.g., by treating withthiophosgene (J. Med. Chem., 18, 90-99 (1975)) orthiocarbonyldiimidazole (Justus Liebigs Ann. Chem., 657 (1962)).

Likewise, starting from the anilines, by treating with NaOH, carbondisulphide, and methyl iodide in processes which are already known fromthe literature, it is possible to prepare the correspondingN-aryldithiocarbamates (Synthesis, 961 (1981)) and, from these in turn,the N-aryldithiocarboximidates of formula IV (Synthesis, 375 (1983)),which can be reacted in the presence of the phenylenediamines of formulaIII at elevated temperatures to give the desired compounds of formula I:

Finally, compounds of formula I can be prepared starting from theanilines and the corresponding 2-substituted benzimidazoles of formula Vby heating.

X in this case is a leaving group, such as, for example, Cl, Br, or SO₃H(J. Org. Chem., 51, 1882 (1986)).

British patent specification 1 171 904 describes a general formula whichwould even allow o,o-disubstitution in the aniline moiety. However,there is no indication of compounds of formula I actually taken intoconsideration which have an o,o-disubstitution pattern, let alone anexperimental description. The compounds described in this British patentspecification 1 174 904 are protected therein as substances havingantibacterial activity. In the case of compounds according to theinvention, it was not possible with the aid of an exemplary compound todetect any antibacterial action, such that the substance class accordingto British patent specification 1 171 904 can be differentiated clearlyfrom the compounds according to the invention, both structurally and inits pharmacological properties.

Furthermore, some of the benzimidazoles according to the invention couldbe constructed from WO 9808818, which are described therein asphospholipase inhibitors. However, no single representative of thisclass of compound is described therein, neither experimentally norpharmacologically.

It was possible to show that compounds of formula I are outstandinginhibitors of the sodium-hydrogen exchanger (NHE)—in particular, of thesodium-hydrogen exchanger of subtype 3 (NHE3).

On account of these properties, the compounds are suitable for thetreatment of diseases which are caused by oxygen deficiency. As a resultof their pharmacological properties, the compounds are outstandinglysuitable as antiarrhythmic medicaments having a cardioprotectivecomponent for infarct prophylaxis and infarct treatment and for thetreatment of angina pectoris, which also preventively inhibit or greatlydecrease the pathophysiological processes in the formation ofischemically induced damage, in particular, in the triggering ofischemically induced cardiac arrhythmias. Because of their protectiveactions against pathological hypoxic and ischemic situations, compoundsof formula I can be used, as a result of the inhibition of the cellularNa+/H+ exchange mechanism, as medicaments for the treatment of all acuteor chronic damage caused by ischemia or diseases induced primarily orsecondarily thereby. This relates to their use as medicaments forsurgical interventions, e.g., in organ transplants, where the compoundscan be used both for the protection of the organs in the donor beforeand during removal, for the protection of removed organs, for example,during treatment with or storage thereof in physiological fluids, andduring surgical transfer to the recipient's body. The compounds arelikewise valuable, protectively acting medicaments when carrying outangioplastic surgical interventions, for example, on the heart and onperipheral vessels. Corresponding to their protective action againstischemically induced damage, the compounds are also suitable asmedicaments for the treatment of ischemias of the nervous system, inparticular, of the CNS, where they are suitable, for example, for thetreatment of stroke or of cerebral edema. Moreover, compounds of formulaI used according to the invention are likewise suitable for thetreatment of forms of shock, such as, for example, of allergic,cardiogenic, hypovolemic, and of bacterial shock.

Furthermore, the compounds induce an improvement in the respiratorydrive and are therefore used for the treatment of respiratory conditionsin the following clinical conditions and diseases: disturbed centralrespiratory drive (e.g., central sleep apneas, sudden infant death,postoperative hypoxia), muscular-related respiratory disorders,respiratory disorders after long-term respiration, respiratory disordersduring adaptation in a high mountainous area, obstructive and mixedforms of sleep apnea, and acute and chronic lung diseases with hypoxiaand hypercapnia.

The compounds additionally increase the muscle tone of the upper airwayssuch that snoring is suppressed.

A combination of an NHE inhibitor with a carboanhydrase inhibitor (e.g.,acetazol-amide), where the latter produces a metabolic acidosis andthereby even increases the respiratory activity, proves advantageous dueto increased action and decreased use of active substance.

It has been shown that compounds used according to the invention have amild laxative action and accordingly can be used advantageously aslaxatives or in the case of threatening intestinal blockage, where theprevention of ischemic damage accompanying blockages in the intestinalarea is particularly advantageous.

The possibility furthermore exists of preventing gallstone formation.

Moreover, compounds of formula I used according to the invention aredistinguished by strong inhibitory action on the proliferation of cells,for example, fibroblast cell proliferation and the proliferation of thevascular smooth muscle cells. Therefore, compounds of formula I aresuitable as valuable therapeutics for diseases in which cellproliferation is a primary or secondary cause, and can therefore be usedas antiatherosclerotic agents against diabetic late complications,cancers, fibrotic diseases such as pulmonary fibrosis, fibrosis of theliver or fibrosis of the kidneys, and organ hypertrophies andhyperplasias, in particular, in prostate hyperplasia or prostatehypertrophy.

Compounds used according to the invention are effective inhibitors ofthe cellular sodium-proton antiporter (Na/H exchanger), which is raisedin numerous diseases (e.g., essential hypertension, atherosclerosis,diabetes), even in those cells which are accessible to measurements,such as, for example, in erythrocytes, platelets, or leukocytes.Compounds used according to the invention are therefore suitable asoutstanding and simple scientific tools, for example, in their use asdiagnostics for the determination and differentiation of certain formsof hypertension, but also of atherosclerosis, diabetes, andproliferative diseases. Moreover, compounds of formula I are suitablefor preventive therapy for the prevention of the genesis of high bloodpressure, for example, of essential hypertension.

It has additionally been found that NHE inhibitors exhibit a favorableinfluence on the serum lipoproteins. It is generally recognized that forthe formation of arteriosclerotic vascular changes, in particular, of aheart disease, excessively high blood lipid levels,‘hyperlipoproteinemia’ is a significant risk factor. For the prophylaxisand the regression of atherosclerotic changes, the lowering of raisedserum lipoproteins therefore assumes extreme importance. Compounds usedaccording to the invention can therefore be used for the prophylaxis andfor the regression of atherosclerotic changes, by excluding a causalrisk factor. With this protection of the vessels against the syndrome ofendothelial dysfunction, compounds of formula I are valuable medicamentsfor the prevention and for the treatment of coronary vasospasms,atherogenesis, and atherosclerosis, left-ventricular hypertrophy anddilated cardiomyopathy, and thrombolytic diseases.

The compounds mentioned are therefore advantageously used for theproduction of a medicament for the prevention and treatment of sleepapneas and muscle-related respiratory disorders; for the production of amedicament for the prevention and treatment of snoring; for theproduction of a medicament for lowering blood pressure; for theproduction of a medicament for the prevention and treatment of diseaseswhich are induced by ischemia and reperfusion of central and peripheralorgans, such as, for example, acute kidney failure, stroke, endogenousstates of shock, and intestinal diseases; for the production of amedicament for the treatment of diabetic late damage and chronic kidneydiseases, in particular, of all kidney inflammations (nephritides) whichare associated with increased protein/albumin excretion; for theproduction of a medicament for the treatment of attack by ectoparasitesin human and veterinary medicine; for the production of a medicament forthe treatment of the diseases mentioned in combination with bloodpressure-lowering substances, typically with angiotensin-convertingenzyme (ACE) inhibitors, with diuretics and saluretics such asfurosemide, hydrochlorothiazide, pseudoaldosterone antagonists, andaldosterone antagonists, and with angiotensin receptor antagonists.

The administration of sodium-proton exchange inhibitors of formula I asnovel medicaments for the lowering of raised blood lipid levels isclaimed, and the combination of sodium-proton exchange inhibitors withmedicaments having blood pressure-lowering and/or hypolipidemic action.

Typically, the compounds mentioned are advantageously used for theproduction of a medicament for the prevention and treatment of sleepapneas and muscle-related respiratory disorders; for the production of amedicament for the prevention and treatment of snoring; for theproduction of a medicament for lowering blood pressure; for theproduction of a medicament for the prevention and treatment of diseaseswhich are induced by ischemia and reperfusion of central and peripheralorgans, such as, for example, acute kidney failure and intestinaldiseases; for the production of a medicament for the treatment ofdiabetic late damage and chronic kidney diseases, in particular, of allkidney inflammations (nephritides) which are associated with increasedprotein/albumin excretion; for the production of a medicament for thetreatment of attack by ectoparasites in human and veterinary medicine;for the production of a medicament for the treatment of the diseasesmentioned in combination with blood pressure-lowering substances,preferably with angiotensin-converting enzyme (ACE) inhibitors, withdiuretics and saluretics such as furosemide, hydrochlorothiazide,pseudoaldosterone antagonists, and aldosterone antagonists, withadenosine receptor modulators, in particular, with adenosine receptoractivators (A2 agonists), and with angiotensin receptor antagonists.

Pharmaceuticals which contain a compound of formula I can in this casebe administered orally, parenterally, intravenously, rectally,transdermally, or by inhalation, the administration being dependent onthe particular clinical picture of the disease. Compounds of formula Ican in this case be administered on their own or together withpharmaceutical excipients, namely both in veterinary and in humanmedicine.

The person skilled in the art is familiar on the basis of his/her expertknowledge with excipients which are suitable for the desiredpharmaceutical formulation. In addition to solvents, gel formers,suppository bases, tablet excipients, and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,or colorants.

For an oral administration form, the active compounds are mixed with theadditives suitable therefor, such as vehicles, stabilizers, or inertdiluents, and brought by the customary methods into the suitableadministration forms, such as tablets, coated tablets, hard gelatincapsules, aqueous, alcoholic, or oily solutions. Inert excipients whichcan be used are, for example, gum arabic, magnesia, magnesium carbonate,potassium phosphate, lactose, glucose, or starch, in particular,cornstarch. In this case, preparation can be carried out both as dry andmoist granules. Suitable oily vehicles or solvents are, for example,vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous administration, the active compoundsused, if desired with the substances customary therefor, such assolubilizers, emulsifiers, or further excipients, are brought intosolution, suspension, or emulsion. Possible solvents are, for example,water, physiological saline solution, or alcohols (e.g., ethanol,propanol, and glycerol). In addition, other possible solvents are sugarsolutions such as glucose or mannitol solutions, or alternatively amixture of the various solvents mentioned.

Pharmaceutical formulations which are suitable for administration in theform of aerosols or sprays are, for example, solutions, suspensions, oremulsions of the active compound of formula I in a pharmaceuticallyacceptable solvent, such as, ethanol or water, or a mixture of suchsolvents.

If required, the formulation can also contain other pharmaceuticalexcipients such as surfactants, emulsifiers, and stabilizers, and apropellant. Such a preparation customarily contains the active compoundin a concentration of approximately 0.1 to 10%, typically, ofapproximately 0.3 to 3%, by weight.

As used here, treatment includes therapy for a particular disease, suchas treating diseases which are influenced by inhibition of the Na⁺/H⁺exchanger. In this respect, treatment can mean successfully eliminatingthe disease, reducing the effects associated with it, and/or reducingits severity. Treatment also includes prevention or prophylaxis of theonset of a disease by treating patients falling into a risk group orcategory for developing a particular disease or by treating patientsafter a successful treatment to prevent reoccurrence of the treateddisease. Those skilled in the art can routinely identify patients likelyto present with a disease, thereby qualifying as candidates forprevention therapy, because of factors such as diet, habits (e.g.,smoking), family history for the disease, etc.

The dose of the active compound of formula I to be administered and thefrequency of administration depend on the potency and duration of actionof the compounds used; moreover, also on the nature and severity of theillness to be treated and on the sex, age, weight, and individualresponsiveness of the mammal to be treated.

On average, the daily dose of a compound of formula I in the case of apatient weighing approximately 75 kg is at least 0.001 mg/kg, typically0.01 mg/kg, to at most 10 mg/kg, usually 1 mg/kg, of body weight. In thecase of acute episodes of the disease, for example, immediately aftersuffering a cardiac infarct, even higher and especially more frequentdoses may also be necessary, e.g., up to 4 individual doses per day. Inparticular, in the case of i.v. administration, for example, in the caseof an infarct patient in the intensive care unit, up to 200 mg per daymay be necessary.

Experimental descriptions and examples:

List of abbreviations used:

R_(t) Retention time TEF Trifluoroacetic acid LCMS Liquidchromatography-mass spectroscopy MS Mass spectroscopy Cl ChemicalIonization RT Room temperature THF Tetrahydrofuran EA Ethyl Acetate

General:

The retention times (R_(t)) indicated below relate to LCMS measurementshaving the following parameters:

stationary phase: Merck Purospher 3 μ2 × 55 mm mobile phase: 95% H₂O(0.05% TEF) → 95% acetonitrile; 4 mm; 95% acetonitrile; 1.5 mm → 5%acetonitrile; 1 min; 0.5 ml/min

EXAMPLE 1 (1H-Benzimidazol-2-yl)-(2,6-dichlorophenyl)amine hydrochloride

(1H-Benzimidazol-2-yl)-(2,6-dichlorophenyl)amine was prepared accordingto methods known from the literature (J. Med. Chem., 18, 90 (1975)).Recrystallization from hot, dilute hydrochloric acid yielded thecorresponding hydrochloride as a colorless solid.

LCMS-R_(t)=3.605 min; MS-Cl: 278.2, 280.0

EXAMPLE 2 2-(2,6-Dichlorophenylamino)-1H-benzimidazol-4-ol hydrochloride

Intermediate 1: 1-(2-Amino-6hydroxyphenyl)-3-(2,6-dichlorophenyl)thiourea

1.0 equivalent of 2,6-dichlorophenyl isothiocyanate was treated with 1.0equivalent of 2,3-diaminophenol and heated to reflux for 1 h. Aftercooling to RT, the precipitate was filtered off with suction, washedwith ether, and dried. The desired thiourea was obtained in a yield of61%. M.p.: 202-204° C.

2-(2,6-Dichlorophenylamino)-1H-benzimidazol-4-ol hydrochloride

Intermediate 1 was dissolved in ethanol and treated with 8 equivalentsof methyl iodide. The mixture was heated to reflux for 8 h. After itcooled to RT, the reaction solution was filtered through activatedcarbon and the filtrate was concentrated in vacuo. The residue wastreated with 0.5 N HCl and the precipitate was filtered off with suctionafter 30 min. The residue was stirred once more with EA and dried. Thetitle compound was isolated in a yield of 47%. M.p.: 333-335° C.

MS(Cl+): 294.1; 296.1

EXAMPLE 3 (1H-Benzimidazol-2-yl)-(2,6-dimethylphenyl)aminetrifluoracetate

2,6-Dimethylaniline (0.5 g) and 2-chlorobenzimidazole (0.63 g) weremixed in a flask and then kept at 200° C. for 2 h. After cooling, theresidue was dissolved out of the flask with 1 N HCl at boiling heat. Thematerial dissolved out was then stirred at RT for 30 min, then theinsoluble material was filtered off with suction and the filtrate wasevaporated. The residue was purified by means of preparative HPLC onRP-18 using acetonitrile/water (0.05% TFA). The clean fractions werecombined, concentrated, and then recrystallized from acetonitrile/water.500 mg of white crystals were obtained.

LCMS-R_(t): 3.30 min; MS (ES+, M+H⁺): 238.1

EXAMPLE 4 (1H-Benzimidazol-2-yl)-(2-chloro-6-methylphenyl)aminehydrochloride

2-Chloro-6-methylaniline (0.46 g) and 2-chlorobenzimidazole (0.5 g) weremixed in a flask and then kept at 170° C. for 30 min. After cooling, theresidue was dissolved out of the flask with 1 N HCl and 10% ethanol atboiling heat. The material dissolved out was then stirred at RT for 30min, then the insoluble material was filtered off with suction and thefiltrate was evaporated. The residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined, the acetonitrile was stripped off, theresidue was adjusted to pH 10 with potassium carbonate solution,extracted three times with EA, and then the combined phases were dried,filtered, and concentrated. The residue was taken up using HCl/water andfreeze-dried. 227 mg of the title compound were obtained.

LCMS-R_(t): 3.71 min; MS (ES+, M+H⁺): 258.0

EXAMPLE 5 (2,6-Dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)aminehydrochloride

2,6-Dichlorophenyl isothiocyanate (0.3 g) and4,5-difluoro-1,2-phenylenediamine (0.21 g) were stirred at RT for 4 h inTHF (15 ml) and then concentrated and dried in a high vacuum. The foamyresidue was dissolved in ethanol and heated to 70° C. with stirring.Methyl iodide (0.73 ml) was then added dropwise.

After three hours, the heating was stopped and the batch was allowed tostand overnight. After concentration, it was taken up using water andEA, and the EA phase was separated off, dried with magnesium sulfate,filtered, and concentrated. The residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined, the acetonitrile was stripped off, theresidue was adjusted to pH 10 with potassium carbonate solution,extracted three times with EA, and then the combined phases were dried,filtered, and concentrated. The residue was taken up using 2 N HCl andfreeze-dried. 55 mg of the title compound were obtained.

LCMS-R_(t): 3.83 m in; MS (Cl+, M+H⁺): 314.1

EXAMPLE 6 (2,6-Dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)aminetrifluoracetate

2,6-Dichlorophenyl isothiocyanate (0.15 g) and 2,3-diaminotoluene (0.09g) were dissolved in THF (15 ml), the solution was stirred at RT for 4 hand then treated with N,N′-dicyclohexylcarbodiimide (0.23 g), and themixture was boiled under reflux for 6 h. After allowing to standovernight, the reaction mixture was concentrated, treated withacetonitrile/water (80:20), the undissolved material was filtered off,and the solution was purified by means of preparative HPLC on RP-18using acetonitrile/water (0.05% TFA). The product-containing fractionswere combined and brought to dryness. Crystallization fromEA/ether/heptane yielded 85 mg of the title compound.

LCMS-R_(t): 3.81 min; MS (ES+, M+H⁺): 292.0

EXAMPLE 7 (1H-Benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)aminehydrochloride

2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5 g) weremixed in a flask and then kept at 170° C. for 30 min. After cooling, theresidue was dissolved out of the flask at boiling heat using 1 N HCl and10% ethanol. The material dissolved out was then stirred at RT for 30min, then the insoluble material was filtered off with suction and thefiltrate was evaporated. The residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined, the acetonitrile was stripped off, theresidue was adjusted to pH 10 with potassium carbonate solution,extracted three times with EA, and then the combined phases were dried,filtered, and concentrated. The residue was taken up using HCl/water andfreeze-dried. 27 mg of the title compound were obtained.

LCMS-R_(t): 3.45 min; MS (ES+, M+H⁺): 262.0

EXAMPLE 8 (1H-Benzimidazol-2-yl)-(2,6-dibromophenyl)aminetrifluoroacetate

2,6-Dibromaniline (0.5 g) was dissolved in absolute dioxane (5 ml),trimethylsilyl chloride (0.22 g) was added dropwise through a septum,and the mixture was then stirred at RT for 2 h. 2-Chlorobenzimidazole(0.3 g) dissolved in dioxane was then added and the mixture was boiledunder reflux. After 4 h, it was cooled, the dioxane was stripped off,and the residue was heated at 190° C. for 10 min. After cooling, theresidue was dissolved out of the flask using 1 N HCl at boiling heat.The insoluble material was then filtered off and the filtrate wasevaporated. The residue was purified by means of preparative HPLC onRP-18 using acetonitrile/water (0.05% TFA). The clean fractions werecombined and freeze-dried. 2.4 mg of the title compound were obtained.

LCMS-R_(t): 3.74 min; MS (ES+, M+H⁺): 369.2

EXAMPLE 9 2-(2,6-Dichlorophenylamino)-5-fluorobenzimidazolehydrochloride

a) 1-(2-Amino-5-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea

A mixture of 4.37 g (0.0346 mol) of 4-fluoro-1,2-diaminobenzene and 7.07g (0.0346 mol) of 2,6-dichlorophenyl isothiocyanate in 150 ml of EA wasboiled under reflux for 3 hours. After distilling off the solvent, theresidue was dissolved in methanol, treated with activated carbon, ⅔ ofthe solvent volume was distilled off, and the thiourea was allowed tocrystallize in an ice bath for a number of hours. 8.9 g of the desiredproduct was obtained. Colorless crystals, 1st m.p.: 175-178° C.; 2ndm.p.: 294-296° C.

MS (ES+, M+H⁺): 329.9

b) 2-(2,6-Dichlorophenylamino)-5-fluorobenzimidazole hydrochloride

1-(2-Amino-5-fluorophenyl)-3-(2,6-dichlorophenyl)-thiourea was dissolvedin ethanol and treated with 8 equivalents of methyl iodide. The mixturewas heated to reflux for 6 h. The solvent was distilled off, the residuewas treated with water, then the mixture was rendered weakly alkaline byaddition of saturated aqueous sodium hydrogencarbonate solution, andextracted. After distilling off the solvent, the residue was purified bycolumn chromatography on silica gel using a mixture of methylenechloride and methanol (10:1). After distilling off the solvent underreduced pressure, the residue was dissolved using EA, and the solutionwas treated with excess ethereal hydrochloric acid. The mixture wasstirred at RT for approximately 30 minutes, and the crystallinesubstance was filtered off and recrystallized from a mixture of EA andethanol. Colorless crystalline product, m.p.: 294-296 ° C.

MS (Cl+, M+H⁺): 296

EXAMPLE 10 2-(2,6-Dichlorophenylamino)-4-fluorobenzimidazolehydrochloride

a) 3-Fluoro-2-nitro-phenylhydrazine

A mixture of 0.01 M 2,6-difluoronitrobenzene and 0.01 M hydrazinehydrate (99% strength) in 30 ml of THF was stirred overnight at RT(exothermic reaction) and the residue was brought to crystallizationafter distilling off the solvent by treating with diisopropyl ether.Crystalline substance, m.p.: 93-95° C.

MS (Cl+, M+H⁺): 172.1

b) 2,3-Diaminofluorobenzene was obtained by hydrogenation of 0.0038 molof 3-fluoro-2-nitrophenylhydrazine in 50 ml of methanol using palladiumon carbon (10% strength) as a catalyst until the absorption of hydrogenended. After filtration, 2,3-diaminofluorobenzene was obtained as ayellow oily substance.

MS (Cl+, M+H⁺): 127.2

c) 1-(2-Amino-6-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained by reaction of 0.011 M 2,3-diaminofluorobenzene with 0.011 M2,6-dichlorophenyl isothiocyanate in 30 ml of anhydrous THF at RT. Afterdistilling off the solvent, the thiourea was brought to crystallizationunder EA. Crystalline solid, m.p.: 315° C.

MS (Cl+, M+H⁺): 330.1

d) 2-(2,6-Dichlorophenylamino)-4-fluorobenzimidazole hydrochloride wasobtained analogously to the procedure described in example 9 by reactionof 1-(2-amino-6-fluorophenyl)-3-(2,6-dichlorophenyl)thiourea with 8equivalents of methyl iodide in ethanol. Colorless crystalline solidhaving a wide melting point range of 268-296° C. with foaming.

MS (Cl+, M+H⁺): 296.1

EXAMPLE 11 2-(2-Trifluoromethyl-6-chlorophenylamino)benzimidazolehydrochloride

a) 1-(2-Aminophenyl)-3-(6-chloro-2-trifluoromethylphenyl)urea wasobtained by reaction of equivalent amounts of 1,2-diaminobenzene and2-trifluoromethyl-6-chlorophenyl isocyanate in anhydrous THF, thedesired urea derivative crystallizing out after a short time. Themixture was stirred at RT for approximately 20 hours and the crystallineprecipitate was filtered off. Decomposition point 310° C.

MS (E+, M+H⁺): 330.1

b) 2-(2-Trifluoromethyl-6-chlorophenylamino)benzimidazole hydrochloride

0.8 g of 1-(2-aminophenyl)-3-(6-chloro-2-trifluoromethylphenyl)urea washeated under reflux conditions for 5 hours in 10 ml of POCl₃, a clearsolution resulting. After distilling off the phosphorus oxychlorideunder reduced pressure, the oily residue was treated with water, slowcrystallization taking place. The crystals were filtered off andchromatographed on silica gel using a mixture of 10 parts ofdichloromethane and 1 part of methanol. After distilling off thesolvent, the residue was dissolved in EA and rendered strongly acidicusing a saturated solution of hydrogen chloride gas in diethyl ether.The crystalline precipitate was filtered off. Colorless to slightlyyellowish crystals. M.p.: 255-288° C.

MS (Cl+, M+H⁺): 312.2

EXAMPLE 12 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazolehydrochloride

a) 1-(2-Amino-5,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained by boiling a mixture of 0.01 M 1,2-diamino-3,4-difluorobenzenewith 0.01 M 2,6-dichlorophenyl isothiocyanate in 50 ml of EA for 4hours. After distilling off the solvent, the thiourea was brought tocrystallization under diisopropyl ether. Crystalline solid. M.p.: >310°C.

MS (Cl+, M+H⁺): 348.0

b) 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazole hydrochloridewas obtained analogously to the procedure described in example 9b from3.2 g of 1-(2-amino-5,6-difluorophenyl)-3-(2,6-dichlorophenyl)thioureaand 10.6 g of methyl iodide. Crystalline solid, m.p.: 228-230° C.

MS (Cl+, M+H⁺): 314.0

EXAMPLE 13 2-(2,6-Dichlorophenylamino)-5-hydroxybenzimidazolehydrobromide

a) 1-(2-Amino-5-methoxyphenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained analogously to the procedure described in example 12a from0.005 M 1,2-diamino-4-methoxybenzene and 0.005 M 2,6-dichlorophenylisothiocyanate. Crystalline solid. M.p.: 164-166° C. and freshcrystallization; decomposition point: 200° C.

MS (ES+, M+): 342.0

b) 2-(2,6-Dichlorophenylamino)-5-methoxybenzimidazole hydrochloride wasobtained analogously to the procedure described in example 9 by reactionof 0.0025 M 1-(2-amino-5-methoxyphenyl)-3-(2,6-dichlorophenyl)thioureawith 0.0205 M methyl iodide in 20 ml of ethanol. After distilling offthe solvent, the residue was dissolved in a little EA, the solution wasrendered strongly acidic using a saturated solution of hydrogen chloridegas in diethyl ether, and the crystals were filtered off after a fewhours. M.p.: 172-174° C.

MS (Cl+, M+H⁺): 308.0

c) 2-(2,6-Dichlorophenylamino)-5-hydroxybenzimidazole hydrobromide

A mixture of 0.05 g of2-(2,6-dichlorophenylamino)-5-methoxybenzimidazole hydrochloride, 0.5 mlof glacial acetic acid, and 0.5 ml of hydrobromic acid (48% strength)was boiled under reflux for 3 hours and the solvent was then distilledoff. The solid residue was brought to crystallization under a little EA.0.02 g of 2-(2,6-dichlorophenylamino)-5-hydroxybenzimidazolehydrobromide was obtained of melting point 265-269° C.

MS (Cl+, M+H⁺): 294.1

EXAMPLE 14 2-(2,6-Dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazolehydrochloride

a) 1-(2-Amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thioureawas obtained by boiling a mixture of 1 g of1,2-diamino-3,4,5,6-tetrafluorobenzene with 1.13 g of 2,6-dichlorophenylisothiocyanate in 30 ml of anhydrous THF for 4 hours. After distillingoff the solvent, the thiourea was brought to crystallization underdiisopropyl ether and 1.88 g of1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichloro-phenyl)thioureawere obtained as a crystalline solid. M.p.: >300° C.

MS (ES+, M+H⁺): 384.06

b) 2-(2,6-Dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazolehydrochloride was obtained analogously to the procedure described inexample 9b from 1.5 g of1-(2-amino-3,4,5,6-tetrafluorophenyl)-3-(2,6-dichlorophenyl)thiourea and4.4 g of methyl iodide and subsequent column chromatography on silicagel using a mixture of 10 parts of EA, 5 parts of n-heptane, 5 parts ofdichloromethane, 5 parts of methanol, and 1 part of aqueous concentratedammonia. Crystalline solid, m.p.: 220-222° C.

MS (Cl+, M+H⁺): 350.2

EXAMPLE 15 2-(2,6-Dichlorophenylamino)-4,6-difluorobenzimidazolehydrochloride

a) 1,2-Diamino-3,5-difluorobenzene was obtained by hydrogenation of 5 gof 2-amino-3,5-difluoronitrobenzene with 0.8 g of palladium catalyst oncarbon at RT and normal pressure. After distilling off the solvent, adark partially crystalline oil was obtained, which was used withoutfurther purification for the preparation of stage b.

b) 1-(2-Amino-4,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea wasobtained by allowing a mixture of 0.01 M 1,2-diamino-3,5-difluorobenzenewith 0.01 M 2,6-dichlorophenyl isothiocyanate in 60 ml of anhydrous THFto stand over the weekend at RT. After distilling off the solvent, thethiourea was brought to crystallization under diisopropyl ether.Crystalline solid, m.p.: 310-314° C.

MS (Cl+, M+H⁺): 348.1

c) 2-(2,6-Dichlorophenylamino)-4,5-difluorobenzimidazole hydrochloridewas obtained analogously to the procedure described in example 9b from 2g of 1-(2-amino-4,6-difluorophenyl)-3-(2,6-dichlorophenyl)thiourea and6.4 g of methyl iodide. Crystalline solid, m.p.: 232-234° C.

MS (Cl+, M+H⁺): 314.2

EXAMPLE 16 (1H-Benzimidazol-2-yl)-(2-chlorophenyl)amine trifluoroacetate

2-Chloraniline (0.5 g) and 2-chlorobenzimidazole (0.6 g) were mixed in aflask and then kept at 225° C. for 2 h. After cooling, the residue wasdissolved out of the flask at boiling heat using 1 N HCl, the insolublematerial was filtered off with suction, and the filtrate was adjusted topH 9-10 using potassium carbonate and concentrated. The residue wastreated with hot methanol, the insoluble material was filtered off, themother liquor was treated with ether, and the precipitate was filteredoff again. The mother liquor was concentrated and the residue wascrystallized again from methanol/ether. After filtering off the crystalswith suction, the mother liquor was concentrated and the residue waspurified by means of preparative HPLC on RP-18 using acetonitrile/water(0.05% TFA). The clean fractions were combined and freeze-dried. 100 mgof the title compound were obtained.

LCMS-R_(t): 3.16 min; MS (Cl+, M+H⁺): 244.0

EXAMPLE 17 (1H-Benzimidazol-2-yl)-(2-trifluoromethylphenyl)aminetrifluoroacetate

2-Aminobenzotrifluoride (0.5 g) and 2-chlorobenzimidazole (0.47 g) weremixed in a flask and then kept at 225° C. for 2 h. After cooling, theresidue was dissolved out of the flask at boiling heat using 1 N HCl andthe insoluble matter was filtered off with suction after cooling. Thefiltrate was concentrated and the residue was purified by means ofpreparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). Theclean fractions were combined and freeze-dried. 52 mg of the titlecompound were obtained.

LCMS-R_(t): 3.65 min; MS (Cl+, M+H⁺): 278.1

EXAMPLE 18 (1H-Benzimidazol-2-yl)-(2-bromophenyl)amine trifluoroacetate

2-Bromoaniline (0.5 g) and 2-chlorobenzimidazole (0.44 g) were reactedaccording to example 17. 117 mg of the title compound were obtained.

LCMS-R_(t): 3.55 min; MS (ES+, M+H⁺): 288.0

EXAMPLE 19 (1H-Benzimidazol-2-yl)-o-tolylamine hydrochloride

2-Methylaniline (0.5 g) and 2-chlorobenzimidazole (0.71 g) were mixed ina flask and then kept at 250° C. for 2 h. After cooling, the residue wasdissolved out of the flask at boiling heat using 1 N HCl, the insolublematerial was filtered off with suction, and the filtrate was evaporated.The residue was purified by means of preparative HPLC on RP-18 usingacetonitrile/water (0.05% TFA). The clean fractions were combined, theacetonitrile was stripped off, the residue was rendered alkaline usingpotassium carbonate solution, extracted three times with EA, and thecombined phases were then dried, filtered, and concentrated. The residuewas taken up using 2 N HCl and the solution was freeze-dried. 110 mg ofthe title compound were obtained.

LCMS-R_(t): 3.54 min; MS (Cl+, M+H⁺): 224.1

Pharmacological Data

Test Description

In this test, the recovery of the intracellular pH (pH_(i)) after anacidification was determined which commences with functional NHE evenunder bicarbonate-free conditions. For this, the pH_(i) was determinedusing the pH-sensitive fluorescent dye BCECF (Calbiochem, the precursorBCECF-AM was employed). The cells were first loaded with BCECF. TheBCECF fluorescence was determined in a “Ratio Fluorescence Spectrometer”(Photon Technology International, South Brunswick, N.J., USA) atexcitation wavelengths of 505 and 440 nm and an emission wavelength of535 nm and converted into the pH_(i) by means of calibration curves. Thecells were incubated in NH₄Cl buffer (pH 7.4) even in the case of BCECFloading (NH₄Cl buffer: 115 mM NaCl, 20 mM NH₄Cl, 5 mM KCl, 1 mM CaCl₂, 1mM MgSO₄, 20 mM Hepes, 5 mM glucose, 1 mg/ml of BSA; a pH of 7.4 is setusing 1 M NaOH). The intracellular acidification was induced by additionof 975 μl of an NH4Cl-free buffer (see below) to 25 μl aliquots of thecells incubated in NH₄Cl buffer. The subsequent rate of pH recovery wasrecorded for two minutes in the case of NHE1, for five minutes in thecase of NHE2, and for three minutes in the case of NHE3. For thecalculation of the inhibitory potency of the substances tested, thecells were first investigated in buffers in which a complete pH recoveryor no pH recovery at all took place. For the complete pH recovery(100%), the cells were incubated in Na+-containing buffer (133.8 mMNaCl, 4.7 mM KCl, 1.25 mM CaCl₂, 1.25 mM MgCl₂, 0.97 mM Na₂HPO₄, 0.23 mMNa₂HPO₄, 5 mM Hepes, 5 mM glucose; a pH of 7.0 is set using 1 M NaOH).For the determination of the 0% value, the cells were incubated in anNa+-free buffer (133.8 mM choline chloride, 4.7 mM KCl, 1.25 mM CaCl₂,1.25 mM MgCl₂, 0.97 mM K₂HPO₄, 0.23 mM KH₂PO₄, 5mM Hepes, 5 mM glucose;a pH of 7.0 is set using 1 M NaOH). The substances to be tested wereapplied in the Na+-containing buffer. The recovery of the intracellularpH at each tested concentration of a substance was expressed in percentof the maximum recovery. The IC value of the respective substance forthe individual NHE subtypes was calculated from the percentage values ofthe pH recovery by means of the program Sigma-Plot.

Results

IC₅₀ [μM], Example (rNHE3) 1 0.53 2 0.47 3 0.64 4 0.49 5 0.78 6 0.39 70.52 8 0.65 9 1.0 10 3.2 11 0.83 12 2.9 13 1.1 14 5.6 15 1.6 16 0.63 173.5 18 1.2 19 3.5

What is claimed is:
 1. A compound selected from:2-(2,6-dichlorophenylamino)-1H-benzimidazol-4-ol;(1H-benzimidazol-2-yl)-(2-chloro-6-methylphenyl)amine;(2,6-dichlorophenyl)-(5,6-difluoro-1H-benzimidazol-2-yl)amine;(2,6-dichlorophenyl)-(4-methyl-1H-benzimidazol-2-yl)amine;(1H-benzimidazol-2-yl)-(2-chloro-6-fluorophenyl)amine;(1H-benzimidazol-2-yl)-(2,6-dibromophenyl)amine;2-(2,6-dichlorophenylamino)-5-fluorobenzimidazole;2-(2,6-dichlorophenylamino)-4-fluorobenzimidazole;2-(2-trifluoromethyl-6-chlorophenylamino)benzimidazole;2-(2,6-dichlorophenylamino)-4,5-difluorobenzimidazole;2-(2,6-dichlorophenylamino)-5 hydroxybenzimidazole;2-(2,6-dichlorophenylamino)-4,5,6,7-tetrafluorobenzimidazole; or2-(2,6-dichlorophenylamino)-4,6-difluorobenzimidazole; or apharmaceutically tolerable salt or trifluoroacetate thereof.
 2. Apharmaceutical composition, which comprises at least one compound ofclaim 1 other than a trifluoroacetate thereof and a pharmaceuticallyacceptable carrier.
 3. A pharmaceutical composition for treatingdisorders of the respiratory system, which comprises an effective amountof at least one compound of claim 1 other than a trifluoroacetatethereof and a pharmaceutically acceptable carrier.
 4. A pharmaceuticalcomposition for treating sleep-related respiratory disorders, whichcomprises an effective amount of at least one compound of claim 1 otherthan a trifluoroacetate thereof and a pharmaceutically acceptablecarrier.
 5. A pharmaceutical composition for treating snoring, whichcomprises an effective amount of at least one compound of claim 1 otherthan a trifluoroacetate thereof and a pharmaceutically acceptablecarrier.
 6. A pharmaceutical composition for treating acute and chronickidney disease, which comprises an effective amount of at least onecompound of claim 1 other than a trifluoroacetate thereof and apharmaceutically acceptable carrier.
 7. A pharmaceutical composition fortreating intestinal disorders, which comprises an effective amount of atleast one compound of claim 1 other than a trifluoroacetate thereof anda pharmaceutically acceptable carrier.
 8. A pharmaceutical compositionfor treating biliary disorders, which comprises an effective amount ofat least one compound of claim 1 other than a trifluoroacetate thereofand a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition for treating ischemic conditions of the peripheral andcentral nervous system and stroke, which comprises an effective amountof at least one compound of claim 1 other than a trifluoroacetatethereof and a pharmaceutically acceptable carrier.
 10. A pharmaceuticalcomposition for treating ischemic conditions of peripheral organs andlimbs, which comprises an effective amount of at least one compound ofclaim 1 other than a trifluoroacetate thereof and a pharmaceuticallyacceptable carrier.
 11. A pharmaceutical composition for treating statesof shock, which comprises an effective amount of at least one compoundof claim 1 other than a trifluoroacetate thereof and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition for treating apatient during surgical operations, which comprises an effective amountof at least one compound of claim 1 other than a trifluoroacetatethereof and a pharmaceutically acceptable carrier.
 13. A pharmaceuticalcomposition for treating illnesses in which cell proliferation is aprimary or secondary cause, which comprises an effective amount of atleast one compound of claim 1 other than a trifluoroacetate thereof anda pharmaceutically acceptable carrier.
 14. A pharmaceutical compositionfor treating disorders of lipid metabolism, which comprises an effectiveamount of at least one compound of claim 1 other than a trifluoroacetatethereof and a pharmaceutically acceptable carrier.
 15. A pharmaceuticalcomposition for treating ectoparasite infection, which comprises aneffective amount of at least one compound of claim 1 other than atrifluoroacetate thereof and a pharmaceutically acceptable carrier.